Genetic epidemiology of hematopoietic cell transplant outcomes

造血细胞移植结果的遗传流行病学

• 批准号: 8940298
• 负责人: Logan G. Spector
• 金额: $ 52.92万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8940298
• 关键词: Affect; Africa; African; Allogenic; Asia; Basic Science; Blood; Cell Death; Cell Survival; Cell Transplants; Cells; Cessation of life; Chromosomes, Human, Pair 6; Climate; Clinical; Clinical Data; Clone Cells; Code; DNA; Data; Disease; Donor Selection; Donor person; Engraftment; Ensure; Eukaryotic Cell; Europe; European; Event; Evolution; Fever; Genes; Genetic; Genetic Polymorphism; Genome; Genotype; Graft-Versus-Tumor Induction; HLA Antigens; Haplogroup; Haplotypes; Health; Hematopoiesis; Hematopoietic; Histones; Human; Immune response; Immune system; In Vitro; Infection; Inherited; Introns; Lead; Link; Longevity; Major Histocompatibility Complex; Marrow; Metabolic; Minnesota; Mitochondria; Mitochondrial DNA; Monozygotic twins; Mortality Determinants; Mus; Nuclear; Organelles; Outcome; Oxidative Phosphorylation; Patients; Peer Review; Persons; Phenotype; Play; Proteins; Recurrent disease; Relapse; Ribosomal RNA; Risk; Role; Selection Criteria; Severities; System; Testing; Time; Transfer RNA; Transplant Recipients; Transplantation; Universities; Validation; Variant; Western Europe; Work; adverse outcome; base; experience; follow-up; genetic epidemiology; graft vs host disease; graft vs leukemia effect; human disease; human leukocyte antigen gene; human stem cells; improved; in vivo; interest; leukemia; migration; mouse model; next generation sequencing; patient population; programs; research study; response; restoration

DESCRIPTION (provided by applicant): Allogeneic hematopoietic cell transplant (allo-HCT) is a time of high metabolic demand. There are immediate needs for restoration of blood formation and response to fever and infection, as well as ongoing challenges of graft versus host disease (GVHD) and possibly graft versus leukemia effects. HCT outcomes have significantly improved with matching refinement of the nuclear DNA human leukocyte antigen (HLA) system, which contains genes encoding for the major histocompatibility complex. However, there were no studies to our knowledge that considered whether mitochondrial DNA and/or mitochondrial DNA matching affected HCT outcomes. Mitochondria (mt) provide cells energy through oxidative phosphorylation (OXPHOS), regulate cell survival and death, and are increasingly thought to functionally influence innate and adaptive immune system responses. Polymorphisms in mtDNA can be grouped into haplotypes (mthaps) that are associated with human global migration. MtDNA contains no introns and therefore polymorphisms can have a direct effect on coding sequences. In support, cybrid (cell clones that have identical nuclear DNA but different mtDNA) studies show evidence of OXPHOS and other functional differences (including immune response) among various mthaps. Numerous association studies have linked specific mthaps to disease occurrence, severity and/or therapy response. We explored whether patient or donor mthaps (H, J, U, T, Z, K, V, X, I, W, K2) were associated with allo-HCT outcomes in 437 patients and 327 donors. We found that certain donor and recipient mthaps (e.g., K, K2, V, W, J, U) may be determinants of mortality, GVHD and/or relapse in HCT recipients. Here, we will validate our initial findings in a much larger, homogenous patient population to further investigate the role of mthaps in allo-HCT. We will obtain DNA and comprehensive clinical data from the National Marrow Donor Program on over 4200 unrelated donors and 4200 HCT recipients and perform NextGen sequencing of the mt genome to establish mthaps. We also will build upon our recent in vivo studies of mt function and explore the functional significance of mthaps in HCT. Our specific aims are to 1) Determine whether recipient or donor mthaps are associated with HCT outcomes; and 2) Investigate whether mismatch between donor and recipient mthaps in HCT is associated with adverse outcomes. A secondary aim is to explore whether mthap phenotypes associated with extreme HCT clinical outcomes (e.g., K2, V) compared to H vary with regard to percent human stem cell engraftment in immunodeficient (NOD-SCID IL2rγnull ("NSG")) mice. Our study will provide necessary validation of our initial results, investigate the role of mismatching of mthaps in HCT outcomes, and provide in vivo and in vitro data of the functional significance of mthaps in the context of HCT. If our preliminary results are confirmed, they could ultimately lead to worldwide implementation of additional selection criteria to identify optimal allo-HCT donors to reduce risk of adverse HCT outcomes.

描述（申请人提供）：同种异体造血细胞移植（Allogeneic hematopoietic cell transplant，简称alloo - hct）是一个代谢需求旺盛的时期。目前迫切需要恢复血液形成和对发烧和感染的反应，以及移植物抗宿主病（GVHD）和可能的移植物抗白血病效应的持续挑战。随着核DNA人类白细胞抗原（HLA）系统的匹配改进，HCT结果显著改善，该系统包含编码主要组织相容性复合体的基因。然而，据我们所知，没有研究考虑线粒体DNA和/或线粒体DNA匹配是否影响HCT结果。线粒体（mt）通过氧化磷酸化（OXPHOS）提供细胞能量，调节细胞存活和死亡，并越来越多地被认为在功能上影响先天和适应性免疫系统反应。mtDNA的多态性可以分为与人类全球迁移相关的单倍型（mthaps）。MtDNA不含内含子，因此多态性对编码序列有直接影响。为了支持这一观点，杂交（细胞核DNA相同但mtDNA不同的细胞克隆）研究表明，各种细胞可能存在OXPHOS和其他功能差异（包括免疫反应）。许多关联研究已经将特定的可能与疾病的发生、严重程度和/或治疗反应联系起来。我们在437名患者和327名供者中探讨了患者或供者的基因（H、J、U、T、Z、K、V、X、I、W、K2）是否与同种异体hct结果相关。我们发现某些供体和受体基因（如K、K2、V、W、J、U）可能是HCT受体死亡率、GVHD和/或复发的决定因素。在这里，我们将在一个更大的、同质的患者群体中验证我们的初步发现，以进一步研究mthaps在同种异体hct中的作用。我们将从国家骨髓捐赠计划中获得超过4200名非亲属供体和4200名HCT受者的DNA和综合临床数据，并对mt基因组进行NextGen测序以建立mthaps。我们也将在最近的mt功能体内研究的基础上，探索mthaps在HCT中的功能意义。我们的具体目标是：1)确定受体或供体基因是否与HCT结果相关；2)调查HCT供体和受体之间的不匹配是否与不良结果相关。第二个目的是探索与极端HCT临床结果相关的mthap表型（例如，K2， V）与H相比，在免疫缺陷（NOD-SCID IL2rγnull（“NSG”））小鼠中，人类干细胞移植的百分比是否有所不同。我们的研究将为我们的初步结果提供必要的验证，调查mthaps错配在HCT结果中的作用，并提供mthaps在HCT背景下功能意义的体内和体外数据。如果我们的初步结果得到证实，它们可能最终导致在全球范围内实施额外的选择标准，以确定最佳的同种异体HCT供体，以降低HCT不良后果的风险。